rs2274976

Variant names:

• chr1-11790870-C-T
• rs2274976
• NM_005957.5:c.1781G>A
• MTHFR p.Arg594Gln

Your query was ambiguous. Multiple possible variants found:

• chr1-11790870-C-T
• chr1-11790870-C-G

Germline classificationCancer classification (beta)

Variant summary

Our verdict is

Benign

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received -14 ACMG points: 0P and 14B. BA1BP4_ModerateBP6_Strong

The NM_005957.5(MTHFR):c.1781G>A (p.Arg594Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0526 (AC=84,877) in the gnomAD database across 1,613,878 control chromosomes, including 2,928 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.139. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R594W: Uncertain_significance (ClinVar VariationId 2040845, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.044 (231 hom., cov: 33)
  • Exomes 𝑓: 0.053 (2697 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 3.20
• Publications: 233 publications found

Genes affected

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

MTHFR Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, ClinGen, G2P

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
• BP6: ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1386 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.1781G>A	p.Arg594Gln	missense	Exon 12 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.1904G>A	p.Arg635Gln	missense	Exon 12 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.1901G>A	p.Arg634Gln	missense	Exon 12 of 12	NP_001397679.1	Q5SNW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.1781G>A	p.Arg594Gln	missense	Exon 12 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.1901G>A	p.Arg634Gln	missense	Exon 12 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.1781G>A	p.Arg594Gln	missense	Exon 12 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.0443 AC: 6735 AN: 151930 Hom.: 230 Cov.: 33

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0555 AC: 13949 AN: 251250 AF XY: 0.0580

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.0434

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.117

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0442

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0535 AC: 78138 AN: 1461830 Hom.: 2697 Cov.: 32 AF XY: 0.0552 AC XY: 40131 AN XY: 727222

African (AFR) AF: 0.0256 AC: 856 AN: 33480

American (AMR) AF: 0.0428 AC: 1912 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 458 AN: 26136

East Asian (EAS) AF: 0.105 AC: 4160 AN: 39700

South Asian (SAS) AF: 0.128 AC: 11058 AN: 86256

European-Finnish (FIN) AF: 0.0184 AC: 984 AN: 53412

Middle Eastern (MID) AF: 0.0182 AC: 105 AN: 5768

European-Non Finnish (NFE) AF: 0.0494 AC: 54948 AN: 1111960

Other (OTH) AF: 0.0606 AC: 3657 AN: 60396

GnomAD4 genome AF: 0.0443 AC: 6739 AN: 152048 Hom.: 231 Cov.: 33 AF XY: 0.0444 AC XY: 3300 AN XY: 74316

African (AFR) AF: 0.0305 AC: 1265 AN: 41448

American (AMR) AF: 0.0431 AC: 658 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3470

East Asian (EAS) AF: 0.120 AC: 620 AN: 5146

South Asian (SAS) AF: 0.148 AC: 711 AN: 4818

European-Finnish (FIN) AF: 0.0160 AC: 170 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0463 AC: 3149 AN: 67974

Other (OTH) AF: 0.0436 AC: 92 AN: 2110

Alfa AF: 0.0471 Hom.: 946

Bravo AF: 0.0427

Asia WGS AF: 0.127 AC: 441 AN: 3478

EpiCase AF: 0.0387

EpiControl AF: 0.0410

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.0908 AC: 11128 AN: 122510

Turkish Variome AF: 0.0385 AC: 257 AN: 6670 Hom.: 17

WBBC (Westlake BioBank for Chinese) pilot AF: 0.105 AC: 937 AN: 8960 Hom.: 49

ABraOM SABE-WGS-1171 AF: 0.0316 AC: 74 AN: 2342 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (3)
-	-	2	not provided (3)
-	-	1	MTHFR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.92
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N
PhyloP100		3.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.042
gMVP		0.22
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2274976;

hg19: chr1-11850927;

COSMIC: COSV57171488;

COSMIC: COSV57171488;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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